Genetic Variant CHRFAM7A:p.Leu179Ser (chr15-30371172-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_139320.2(CHRFAM7A):c.536T>C(p.Leu179Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000693 in 144,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000069 ( 0 hom., cov: 24)

Consequence

CHRFAM7A
NM_139320.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.59

Variant links:

Genes affected

CHRFAM7A (HGNC:15781): (CHRNA7 (exons 5-10) and FAM7A (exons A-E) fusion) The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The family member CHRNA7, which is located on chromosome 15 in a region associated with several neuropsychiatric disorders, is partially duplicated and forms a hybrid with a novel gene from the family with sequence similarity 7 (FAM7A). Alternative splicing has been observed, and two variants exist, for this hybrid gene. The N-terminally truncated products predicted by the largest open reading frames for each variant would lack the majority of the neurotransmitter-gated ion-channel ligand binding domain but retain the transmembrane region that forms the ion channel. Although current evidence supports transcription of this hybrid gene, translation of the nicotinic acetylcholine receptor-like protein-encoding open reading frames has not been confirmed. [provided by RefSeq, Jul 2008]

CHRFAM7A links:

LOC105370751 (HGNC:):

LOC105370751 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRFAM7A	NM_139320.2 link	c.536T>C	p.Leu179Ser	missense_variant	Exon 8 of 10	ENST00000299847.7	NP_647536.1	Q494W8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHRFAM7A	ENST00000299847.7 link	c.536T>C	p.Leu179Ser	missense_variant	Exon 8 of 10	1	NM_139320.2	ENSP00000299847.3	Q494W8
CHRFAM7A	ENST00000401522.7 link	c.263T>C	p.Leu88Ser	missense_variant	Exon 9 of 11	1		ENSP00000385389.3	A0A0A6YYA8
CHRFAM7A	ENST00000397827.7 link	c.263T>C	p.Leu88Ser	missense_variant	Exon 7 of 9	5		ENSP00000380927.3	A0A0A6YYA8
CHRFAM7A	ENST00000692430.1 link	n.488T>C		non_coding_transcript_exon_variant	Exon 3 of 5

Frequencies

GnomAD3 genomes

AF:

0.00000693

AC:

AN:

144302

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000693

AC:

AN:

144302

Hom.:

Cov.:

AF XY:

0.0000143

AC XY:

AN XY:

70158

show subpopulations

Gnomad4 AFR

AF:

0.0000266

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 09, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.536T>C (p.L179S) alteration is located in exon 8 (coding exon 6) of the CHRFAM7A gene. This alteration results from a T to C substitution at nucleotide position 536, causing the leucine (L) at amino acid position 179 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;.;.

Eigen

Uncertain

0.44

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.97

D;D;.

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Pathogenic

3.9

H;.;.

PROVEAN

Pathogenic

-5.3

D;D;D

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.031

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.97

MutPred

0.85

Gain of catalytic residue at L179 (P = 0.0696);.;.;

MVP

0.74

ClinPred

1.0

GERP RS

2.6

Varity_R

0.78

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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